Fecal Microbiota Transplantation For C.Diff Associated diarrhea and beyond Ramy Eid, MD Gastrointestinal Specialists, Inc
Introduction and Definitions Gut microbiota Evolution and role Immune system function Gut homeostasis Symbiosis Dysbiosis C. difficile infection (CDI)
Normal intestinal flora Human colonic microbiota 100 trillion bacteria (plus fungi, viruses) 500-1000 different species 60% of stool volume is bacteria Normally protects against invasive pathogens, infection, Produce vitamins Assist in digestion of non-digestible fiber Maintain colon health through production of free fatty acids Modulate the colonic immune system
C.difficile infection Exposure to C. difficile spores Exposure to antibiotics Germination and colonization of the spores and vegetative outgrowth Expression of the toxins A and B Epithelial damage and symptomatic infection
C. difficile infection Self limited Diarrhea, leukocytosis, fever, or pseudomembranous colitis Limited to one course of antibiotics Recurrent or relapsing C.difficile infection Severe and fulminant disease Ileus, megacolon, lactic acidosis, renal failure, septic shock, death
C. Diff has become more drug-resistant & more deadly
C. difficile infection Risk factors Recent antibiotic intake Age over 65 Recent hospitalization Proton pump inhibitors use Underlying medical disorders, renal insufficiency Concomitant antibiotics during treatment for C.difficile infection Lack of antibody-mediated immune response to toxin B
Epidemiology Most common infectious cause of healthcare-associated diarrhea At least half a million infections a year Over 83,000 experienced at least one recurrence Close to 30,000 death per year Transmission of spores, resistant to heat, acid, antibiotics and most surface cleaners, except bleach Now more than ¼ are community acquired Increased healthcare cost: $1.5 billion dollars per year
C.difficile infection Treatment Antibiotics Mild to moderate disease Oral antibiotics Metronidazole Vancomycin Fidaxomicin Severe Disease Oral vancomycin and IV metronidazole Oral fidaxomicin Recurrent or relapsing disease Pulsed oral antibiotic therapy Fecal microbiota transplantation More aggressive and virulent strains are developing Increasing number of infections
What is FMT Transfer and implantation of stool and bacteria from the colon of a healthy person to the colon of a person with a certain disease to affect the cure of that disease.
FMT Rx Guidelines 2018 ACG: American College of Gastroenterology IDSA: Infectious Diseases Society of America SHEA: Society for Healthcare Epidemiology of America ESCMID: European Society of Clinical Microbiology and Infectious Diseases WSES: World Society of Emergency Surgery ASID: Australasian Society for Infectious Diseases
Indications for FMT ≥ 3 Recurrences of mild/moderate CDI and failure to respond to standard Rx ≥2 Episodes of CDI resulting in hospitalization and significant morbidity Moderate CDI with no response to standard therapy for at least 1 week Severe CDI with no response to standard therapy after 48 hours
Donor selection Intimate Friend Unrelated volunteer Over the age 18 Family members Men preferred over women? (autoimmune diseases, IBS) Pre-screened healthy donor pool
Donor screening Use same exclusions as for blood product donation Screen donor for any illness – generally want someone who is healthy and on no medications Screen for hepatitis A, B, C, HIV, H.pylori, syphilis, C.difficile, Giardia, E.coli, Salmonella, Shigella, Campylobacter infections Can be an individual familiar to the patient or familiar to the MD
Stool preparation Stool is collected from the donor, processed to create a liquid suspension in water, filtered for large particulates Stool can be frozen and used later with similar efficacy
Administration Small bowel upper endoscopy to the jejunum Nasojejunal tube placement Colonoscopy Retention enemas Oral capsules
OpenBiome Frozen stool from universal donor(s) Stool bank Upper, lower, capsules (30)
Clinical scenario Product/Route Lower, upper, capsules Multiple lower ± upper Upper Typical recurrence Toxic megacolon/Ileus Aged, infirm, incontinent
Safety of FMT SHORT-TERM Risk of aspiration if not delivered deep into upper small intestine Risk of acquiring infection from donors – rare, single case reports Risk of complications from sedation and endoscopy – bleeding, perforation, transmission of other infections: 1/1000-1/10,000 Does not impact liver transplantation screening or status
Safety of FMT LONG-TERM Complex interplay between gut microbiome and host Risk of developing conditions of the donor? Intestinal microbiota has been associated with colon cancer, diabetes, obesity and atopic disorders
Efficacy data in CDI Success rates depend slightly on route of delivery Enema 80-85% Upper GI 80-85% Colonoscopy to the right colon 90-95% Usually see control of diarrhea symptoms within 48-96 hours MGH study, open label, relapsing C.Dff 15 frozen pills, orally over 2 consecutive days 90% response rate
Frozen Fecal Material Randomized trial : 219 patients 6 Canadian academic medical centers Frozen/thawed vs fresh stool for R-CDI Frozen Fresh Per-protocol analysis 83.5% 85.1% Advantages of frozen FMT: Availability, efficacy, safety, cost, data collection Lee CH, et al. JAMA 2016
FMT: Fresh, Frozen, or Lyophilized (RDBCT of 72 pts with R-CDI Cure Rates Microbial diversity Reconstitution Fresh 100% By Day 7 Frozen 83.3% Lyophilized 69.6% By Day 30 Overall 87% Jiang, et al. Aliment Pharmacol Ther 2017
Public Stool Bank* 2050 pts from 633 health care facilities 50 States, 7 countries CDI Clinical Cure Upper (30 ml) Lower (250) n= 15% n= 85% Recurrent (1542) 85.9% 79.5% 87.0% Severe (90) 83.3% 88.0% 81.5% Mixed (259) 79.2% 66.7% 80.0% Refractory (159) 74.2% 69.7% 75.4% Overall 84% 74.1% 85.8% 42 AEs, none definitely related to FMT *OpenBiome, Medford, MA Poster 2120:Osman, et al. ID week 2016
FMT Capsules Author Dose #Patients Cure Louie, et al 24-34 caps 27 100% Youngster, et al 30 caps (15 x 2d) 180 91% Khanna, et al 15 93% Allegretti, et al 30 caps 24 94% Hirsch, et al 6-22 caps 19 88% Staley, et al 49 ID week 2013 BMC Med 2016 JID 2016 DDW 2016 BMC Infect Dis 2015 Am J Gastro 2017
Primary Cure Rates of FMT for CDI Meta-analysis (18 studies, 611 patients) 91.2% Overall Lower: 93.2% Upper:81.8% Younger: 99.4% Older: 87% Li, et al. Aliment Pharmacol Ther 2016
Recurrence Rates of FMT for CDI Meta-analysis (18 studies, 611 patients) 5.5% Overall Lower:6.0% Upper:8.2% Younger: 4.6% Older: 9.3% Li, et al. Aliment Pharmacol Ther 2016
FMT for R-CDI 37 studies (7 RCTs and 30 case series) FMT was more effective than vancomycin Clinical resolution rates (all studies): 92% Lower tract FMT more effective than upper tract FMT No difference between efficacy of fresh and frozen stool Consecutive FMTs after failure of First FMT ====> Incremental effect Serious AEs are uncommon
How often does CDI recur after FMT? Author Year Recurrence Rate # Patients Mean Interval Brandt, et al 2012 10% 8/77 17 months Khanna, et al 2015 10.5% 25/238 14 months Fischer, et al 2016 16/152 16 months After FMT, long term rates of R-CDI with antibiotic use is low But not as low as without antibiotics.
Predictors of failure after FMT for R-CDI Advanced age Underlying disease (COPD, renal failure…) Hospital acquisition Inpatient status Severe/complicated CDI Immunocompromised Maximum WBC during R-CDI Administration of antibiotics during R-CDI PPI use
Role for Probiotics to prevent R-CDI May be effective at preventing CDI in pts on abx without history of CDI Rx with probiotics closer to the first dose of abx decreases the risk of CDI by 50% in hospitalized patients There is insufficient data to recommend probiotics for primary prevention of CDI There is potential risk for probiotics to cause disseminated infections in hospitalized patients
FMT in severe, complicated CDI 57 consecutive inpatients 91% (52/57) clinical cure at 1 month No difference between fresh and frozen fecal material No SAEs Patients with severe or fulminant CDI and extensive pseudomembranes tend to respond poorly to a single FMT when anti-CDI antibiotics were held 53% pts cured by single FMT 28% pts needed 2 FMTs 11% pts required ≥ 3 FMTs Sequential FMT for severe or complicated CDI is promising and may be preferred over colectomy in certain patients
FMT in Diseases other than Clostridium difficile
FMT in inflammatory bowel disease Dysbiosis characterized by decreased diversity of species Decreased Bacteroidetes phylum and Lachnospiraceae Increase in Proteobacteria and Actinobacteria Low levels of Faecalibacterium prausnitzii Mixed results so far Quality of studies Variety of patient population Concomitant medications
FMT in inflammatory bowel disease UC patients less likely to achieve clinical remission Meta-analysis: 45% clinical remission rate Younger patients Crohn’s disease Short-term effect? Side effects: bloating, flatulence, vomiting, diarrhea, abdominal tenderness Flares have been described
FMT in inflammatory bowel disease 75 patients with UC , randomized to weekly FMT or water enemas for 6 weeks 24% achieved remission 5% with placebo 50 patients: Donor FMT or autologous FMT No statistically significant difference in clinical or endoscopic remission
FMT in Obesity Role of gut microbiome in obesity Transfer of gut microbiota from lean and obese in ex-germ free mice Antibiotic treatment in early life can predispose to obesity in animal models Transfer following Roux-en-Y gastric bypass Weight loss Greater amount of short chain fatty acids in lean mice Increase neuro-hormonal axis: Increase energy expenditure Improved insulin sensitivity
FMT in irritable bowel syndrome Decreased microbial diversity Early studies reported improvement Small, uncontrolled series with high risk of bias
FMT in other indications Metabolic syndrome Type II diabetes Fatty liver disease Multidrug resistant organism eradication Hepatic encephalopathy Pediatric allergy disorders Association ≠ Causation
Regulatory issues Worldwide variation Australia and Europe no regulation so far Canada: FMT “New Biologic Drug” FDA: Biological product Donor eligibility, stool processing and infusion, fall under FDA jurisdiction
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